Rhodium-Catalyzed/Copper-Mediated Tandem C(sp2)-H Alkynylation and Annulation: Synthesis of 11-Acylated Imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olates from 2H-[1,2′-Bipyridin]-2-ones and Propargyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.6b00177

A rhodium-catalyzed/copper-mediated tandem C(sp²)-H alkynylation and intramolecular annulation of 2H-[1,2′-bipyridin]-2-ones with propargyl alcohols for the synthesis of 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olates is described.

Full text of DOI:10.1021/acs.orglett.6b00177

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed/Copper-Mediated Tandem C(sp2)−H
Alkynylation and Annulation: Synthesis of 11-Acylated
Imidazo[1,2‑a:3,4‑a′]dipyridin-5-ium-4-olates from 2H‑[1,2′-
Bipyridin]-2-ones and Propargyl Alcohols
Ting Li,*,†,‡ Zhiqiang Wang,† Kun Xu,† Wenmin Liu,† Xu Zhang,† Wutao Mao,† Yongming Guo,†
Xiaolin Ge,† and Fei Pan‡
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, China
‡Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed/copper-mediated tandem C(sp2)−H alkynylation and intramolecular annulation of 2H-
[1,2′-bipyridin]-2-ones with propargyl alcohols for the synthesis of 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olates is
described.
2-Pyridones represent an important class of nitrogen-containing
heterocycles in biologically active compounds and versatile
synthetic intermediates in organic synthesis.1 As such, there is
continuing interest in new synthetic methods that provide
selective access to substituted 2-pyridone derivatives.2 To date, a
number of approaches that allow regioselective functionalization
of 2-pyridones, including alkylation,3 arylation,4 and alkenyla-
tion,5 at the C-3, C-5, or C-6 positions of the 2-pyridone ring,
have been successfully reported. However, despite certain
advances, regioselective alkynylation of 2-pyridones still remains
a challenge. The tedious procedure and harsh reaction conditions
for prefunctionalization of 2-pyridones prevent the use of
Sonogashira-type coupling reactions for introducing alkynyl
functionality. On the other hand, alkynes, as easily accessible
building blocks in organic synthesis, provide chemists with a
fertile testing ground for the construction of complex organic
molecules.6 In this regard, solutions for the alkynylation of 2-
pyridones are highly desirable as they would enable access to an
important range of natural and unnatural products containing a
2-pyridone moiety.
Recently, transition-metal-mediated C−H alkynylation for the
introduction of alkynyl functionality7 has received much
attention from the synthestic community. It is appealing to
employ terminal alkynes as alkynylation reagents in C−H
alkynylation. Due to the polymerization of terminal alkynes
under high temperatures, only a narrow scope of electron-rich
heteroarenes such as thiophenes or highly electron-poor arenes
with reactive acidic C−H bonds has been successfully achieved.8
Instead, haloalkynes9 and terminal alkynes bearing a bulky silyl
group10 have been used, while the substrate scope still remains
limited. The recently reported benziodoxolone-based hyper-
valent iodine reagent proved to be an efficient and general
alkynylation reagent. However, it was only suitable for
triisopropylsilyl-based alkynyliodonium reagents, while aryl- or
alkyl-substituted substrates could not afford the alkynylation
products.11 It is worth noting that tert-propargyl alcohols have
been involved in Sonogashira-type reactions as masked terminal
alkynes.12 Moreover, Miura discovered that [Rh(OH)(COD)]2
could catalyze regio- and stereoselective homocoupling of γ-
substituted tert-propargyl alcohols via β-carbon elimination with
the liberation of a ketone in which an alkynyl rhodium generated
in situ was proposed as the key intermediate.13 Inspired by these
results, we were thus prompted to design the rhodium-catalyzed
direct C−H alkynylation of 2-pyridones utilizing propargyl
alcohols as the alkynyl coupling partner.
In an attempt to obtain the direct C-6 selective C−H
alkynylation product of 2H-[1,2′-bipyridin]-2-one, a red
compound, 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-
4-olate, was isolated serendipitously (Scheme 1). Herein, we
report a rhodium-catalyzed/copper-mediated tandem C(sp2)−
H alkynylation and intramolecular annulation of 2H-[1,2′-
bipyridin]-2-ones with propargyl alcohols, leading to the
formation of 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-
4-olates in good to excellent yields.
Initial experiments were performed with 2H-[1,2′-bipyridin]-
2-one 1a and 2-methyl-4-phenyl-3-butyn-2-ol 2a′ in the presence
of 1.5 mol % of [RhClCOD]214 and 2.2 equiv of Cu(OAc)2·H2O
Received: January 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00177
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Rhodium-Catalyzed/Copper-Mediated Synthesis
Scheme 2. Substrate Scope for Propargyl Alcohols
of 11-Acylated Imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olates
as oxidant. The unexpected red compound 3aa, which contains
the 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium skeleton,
was generated in about 39% isolated yield instead of the desired
alkynylation product (Table 1, entry 1). The definite structure of
a
Table 1. Optimization of the Reaction Conditions
a
Conditions: A mixture of derivative 1a (0.20 mmol), propargyl
alcohols 2 (0.40 mmol), [RhCl(COD)]2 (1.5 mol %), Cu(OAc)2·H2O
(0.44 mmol, 2.2 equiv), and toluene (2 mL) was added to a Schlenk
tube under an air atmosphere. Then the mixture was stirred at 125 °C
(bath temperature, preheated) under air for 4 h. Isolated products
based on 1a.
a
Scheme 3. Subsrate Scope for 2H-[1,2′-Bipyridin]-2-ones
entry
substrate
conditions
yield (%)
1
2
2a′
2a
[RhClCOD]2, 125 °C, PhMe
[RhClCOD]2, 125 °C, PhMe
[RhClCOD]2, 125 °C, PhMe
[RhClCOD]2, 125 °C, PhMe
[RhClCOD]2, 125 °C, PhMe
[RhClCOD]2, 125 °C, PhMe
[Rh(CO)2Cl]2, 125 °C, PhMe
[Rh(OH)COD]2, 125 °C, PhMe
Rh2(OAc)4, 125 °C, PhMe
[Cp*RhCl2]2, 125 °C, PhMe
Cp*Rh(OAc)2, 125 °C, PhMe
[RhClCOD]2, 125 °C, PhMe
Cu(OAc)2·H2O, 125 °C, PhMe
[RhClCOD]2, 125 °C, PhCl
[RhClCOD]2, 125 °C, DCE
[RhClCOD]2, 125 °C, DMF
39
86
12
34
0
3
2b′
2c′
2d′
2e′
2a
4
5
6
8
7
42
76
64
39
37
0
8
2a
9
2a
10
11
2a
2a
b
12
2a
c
13
2a
0
14
15
16
2a
62
55
trace
2a
2a
a
Conditions: A mixture of derivative 1 (0.20 mmol), propargyl
a
Conditions: 1a (0.20 mmol), 2 (0.40 mmol, 2 equiv), [M] (1.5 mol
alcohols 2a (0.40 mmol), [RhCl(COD)]2 (1.5 mol %), Cu(OAc)2·
H2O (0.44 mmol, 2.2 equiv), and toluene (2 mL) was added to a
Schlenk tube under an air atmosphere. Then the mixture was stirred at
125 °C (bath temperature, preheated) under air for 4 h. Isolated
products based on 1.
%), Cu(OAc)2·H2O (2.2 equiv), and solvent (2 mL) under air for 4 h.
Yield of isolated products based on 1a. Reaction performed in the
absence of Cu(OAc)2·H2O. Reaction performed in the absence of
[RhClCOD]2.
b
c
3 was confirmed by X-ray crystallographic studies of 3aa and 3ga,
as shown in Scheme 2 and Scheme 3 (vide infra). The formation
of the 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium skeleton
is interesting. To the best of our knowledge, efficient
construction of imidazo[1,2-a:3,4-a′]dipyridin-5-ium, a recur-
ring structural motif found in many pharmaceuticals and
functional materials, has rarely been reported.15 However,
further studies to increase the yield of product 3aa by using
2a′ as the alkynylation reagent failed. To our delight, when 1,3-
diphenylprop-2-yn-1-ol 2a was used as the alkynylation reagent
instead, the reaction was accelerated and compound 3aa could be
isolated in 86% yield (entry 2). To the best of our knowledge, this
represents the first report that 1,3-diphenylprop-2-yn-1-ol 2a
could be used as alkynylation reagents for the introduction of the
alkynyl functionality via Csp3−Csp single bond cleavage.16
Ongoing studies to try other propargyl alcohols as alkynylation
reagents instead of 2a revealed that 2a was the best C−H
alkynylation reagent for 2H-[1,2′-bipyridin]-2-one (entries 3−
5). We have also examined the possibility of employing a
terminal alkyne instead of 2a for this transformation, which gave
3aa in only 8% yield (entry 6). Further investigation of the
rhodium catalyst precursors demonstrated that [RhCl(COD)]2
was the best choice for this transformation (entries 7−11).
Control experiments revealed that no desired product 3aa was
B
DOI: 10.1021/acs.orglett.6b00177
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
detected in the absence of either [RhCl(COD)]2 or Cu(OAc)2·
H2O (entries 12 and 13). Investigation on solvent effects
indicated that toluene was the most suitable solvent (entries 14−
16).
Scheme 4. Mechanism Studies
Under the optimized reaction conditions in Table 1, we sought
to further explore the scope and limitation of this transformation.
First, a series of propargyl alcohols were investigated (Scheme 2).
To our satisfaction, propargyl alcohols containing electron-
donating or electron-withdrawing substituents such as OMe, Et,
Cl, and F at the para position on the phenyl ring were well-
tolerated to provide the corresponding products in good yields
(3ab−3ae), while substrate 2e showed poor conversion (<10%).
Substrates bearing a Me group at the meta or para position on the
phenyl ring proceeded smoothly (3ag, 3ah), while that with a Me
group at the ortho position failed to yield the desired product 3ai,
possibly due to the steric hindrance. It is noteworthy that the
methodology could be further extended to thiophene-containing
substrate 2j to afford the corresponding product 3aj, which was
isolated in about 51% yield. Further studies revealed that
aliphatic propargyl alcohol 2k was not compatible with this
transformation, and only trace 3ak could be detected in the
reaction mixture.
Consequently, the scope for the 2H-[1,2′-bipyridin]-2-ones
was further investigated (Scheme 3). First, the influence of
substituent on the pyridyl directing group was investigated.
Gratifyingly, it was found that installation of a Me substituent on
the pyridyl C-2 or C-3 position furnished product 3ca or 3da in
63 and 71% yield, respectively. In contrast, when the C-1 or C-4
position of the pyridyl directing group was blocked with a Me
group, the reaction was completely suppressed, probably as a
result of steric factors (3ba and 3ea). Besides, the reaction also
accommodated CF3 and F groups on the pyridyl directing group
(3fa and 3ga in 51 and 81% yields). The generality of the 2-
pyridone ring was next examined. Installation of a Me group at
the C-3 or C-4 position on the 2-pyridone ring had a negative
influence on the transformation (3ha and 3ia). In contrast, when
the Me group was at the C-5 position, the reaction was
completely suppressed (3ja). Moreover, reaction of other 2H-
[1,2′-bipyridin]-2-ones was also investigated. 2H-[1,2′-Bipyr-
idin]-2-ones with a substituent group including F, Cl, or CF3 at
C-3 position of the 2-pyridone ring were compatible with this
transformation, thus affording products 3ka, 3la, and 3ma in
good yields. Besides, when the C-4 position of the 2-pyridone
ring was fixed with a substituent such as Cl, CF3, or OBn, the
reaction also worked well to provide 3na, 3oa, and 3pa in 73, 86,
and 71% yields, respectively.
It is reasonable to believe that the reaction first underwent C−
H alkynylation of substrate 1a,17 followed by intramolecular
annulation of the resulting alkyne to generate the target 3aa. To
gain insight into the C−H cleavage step, substrate 1a was treated
with excess CD3OD (10 equiv) for 4 h under standard reaction
conditions, and partial D exchange (28%) was detected at the C-
6 position (Scheme 4(1)). This result clearly indicated that a
reversible deprotonative C−H bond activation step might exist in
the transformation. Besides, by employing deuterium-labeled
compound [D1]-1a as the substrate, the kinetic isotope effect
(KIE) of the transformation was tested. The KIE value was
determined to be 3.6, indicating that the C−H bond cleavage was
the rate-determining step in the transformation (Scheme 4(2)).
Moreover, competition experiments with substrates bearing
varied electronic properties were also investigated, and formation
of products derived from electron-deficient 2H-[1,2′-bipyridin]-
2-one 1g and electron-rich propargyl alcohol 2b was favored in
this transformation (Scheme 4(3)).
Moreover, several controlled experiments were performed to
gain insight into the annulation transformation (see Supporting
Information (SI)). First, we carried out the reaction under N2
atmosphere and found that the reaction turned messy with only
trace 3aa isolated. In contrast, the reaction conducted using
distilled PhMe under dry O2 worked well to provide 3aa in 84%
yield. Besides, the reaction in the presence H218O under O2 was
also conducted, and the 18O-atom-containing product [18O]-3aa
was not detected at all. These results indicated that O2 in air was
vital to the transformation, and the source of oxygen atom in 3aa
was from O2 under air rather than from water. Besides, when a
stoichiometric amount of radical inhibitor, TEMPO, was added
to the reaction, only trace 3aa could be isolated, suggesting that
the reaction proceeds through a radical process. Reaction of 1a
with ethyl 2-diazoacetate as a carbene acceptor was also
conducted to afford 3aa with the core containing 2-pyridone,
thereby indicating that metal carbene intermediate was not
involved in the transformation.
Given the above results and previous reports,18 a possible
mechanism for the transformation of the alkynylation product to
the final product 3aa was proposed (Scheme 5). First,
complexation of Cu(OAc)2 with the alkynylation product yields
intermediate I, which is followed by the intramolecular
cyclization to deliver intermediate II. Oxidation of II with O2
in air generates the peroxycopper III with the aid of the oxidative
additive. Reductive elimination of intermediate III gives rise to
the peroxycopper complex IV.18 Finally, the O−O bond cleavage
of IV and consequent oxidization affords V, which undergoes
rearrangement to afford product 3aa finally.
Finally, 5 mmol scale reactions were conducted using 1a and
1o as substrates, and the reaction proceeded smoothly to give
products 3aa and 3oa in 81 and 84% yields, respectively (Scheme
C
DOI: 10.1021/acs.orglett.6b00177
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Hill, M. D.; Movassaghi, M. Chem. - Eur. J. 2008, 14, 6836.
(b) Bengtsson, C.; Almqvist, F. J. Org. Chem. 2010, 75, 972.
(3) (a) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2009, 131, 15996. (b) Tamura, R.; Yamada, Y.; Nakao, Y.; Hiyama, T.
Angew. Chem., Int. Ed. 2012, 51, 5679. (c) Nakatani, A.; Hirano, K.;
Satoh, T.; Miura, M. Chem. - Eur. J. 2013, 19, 7691.
Scheme 5. Proposed Mechanism
(4) (a) Chen, Y.; Wang, F.; Jia, A.; Li, X. Chem. Sci. 2012, 3, 3231.
(b) Nakatani, A.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2014, 79,
1377. (c) Anagnostaki, E. A.; Fotiadou, A. D.; Demertzidou, V.;
Zografos, A. L. Chem. Commun. 2014, 50, 6879.
(5) Itahara, T.; Ouseto, F. Synthesis 1984, 1984, 488.
(6) Acetylene Chemistry: Chemistry, Biology, and Material Science;
Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH:
Weinheim, Germany, 2005.
(7) (a) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem.
Soc. Rev. 2009, 38, 3242. (b) Herrerías, C. I.; Yao, X.; Li, Z.; Li, C.-J.
Chem. Rev. 2007, 107, 2546. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147. (d) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111,
1293. (e) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
Rev. 2011, 40, 4740. (f) Ackermann, L. Acc. Chem. Res. 2014, 47, 281.
(8) (a) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc.
2010, 132, 2522. (b) Kim, S. H.; Yoon, J.; Chang, S. Org. Lett. 2011, 13,
1474. (c) Jie, X.; Shang, Y.; Hu, P.; Su, W. Angew. Chem., Int. Ed. 2013,
52, 3630. (d) Shang, M.; Wang, H.-L.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. J.
Am. Chem. Soc. 2014, 136, 11590. (e) Dong, J.; Wang, F.; You, J. Org.
Lett. 2014, 16, 2884. (f) Liu, Y.-H.; Liu, Y.-J.; Yan, S.-Y.; Shi, B.-F. Chem.
Commun. 2015, 51, 11650.
6). Moreover, we also characterized the UV−vis absorption of
several representative products and found that the synthesized
Scheme 6. Gram-Scale Synthesis of Compounds 3aa and 3oa
(9) (a) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc.
2007, 129, 7742. (b) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc.
2011, 133, 12984. (c) He, J.; Wasa, M.; Chan, K. S. L; Yu, J.-Q. J. Am.
Chem. Soc. 2013, 135, 3387.
(10) (a) Kim, S. H.; Park, S. H.; Chang, S. Tetrahedron 2012, 68, 5162.
(b) Liu, Y.-J.; Liu, Y.-H.; Yin, X.-S.; Gu, W.-J.; Shi, B.-F. Chem. - Eur. J.
2015, 21, 205.
(11) (a) Tolnai, G. L.; Ganss, S.; Brand, J. P.; Waser, J. Org. Lett. 2013,
15, 112. (b) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed.
2009, 48, 9346. (c) Feng, C.; Loh, T.-P. Angew. Chem., Int. Ed. 2014, 53,
2722. (d) Xie, F.; Qi, Z.; Yu, S.; Li, X. J. Am. Chem. Soc. 2014, 136, 4780.
(12) (a) Nishimura, T.; Araki, H.; Maeda, Y.; Uemura, S. Org. Lett.
2003, 5, 2997. (b) Li, T.; Wang, Z.; Zhang, M.; Zhang, H.-J.; Wen, T.-B.
Chem. Commun. 2015, 51, 6777.
polycyclic compounds showed strong UV−vis absorption in the
range of 420−500 nm (see SI).
In summary, we have presented a convenient method for the
synthesis of 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-
olate via rhodium-catalyzed/copper-mediated tandem C(sp2)−
H alkynylation and intramolecular annulation of 2H-[1,2′-
bipyridin]-2-ones with propargyl alcohols. The use of readily
available substrates, a simple procedure, and mild reaction
conditions (in particular, no requirement to exclude moisture or
air) renders this method potentially useful for the synthesis of
imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate skeletons in organ-
ic synthesis.
(13) Funayama, A.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2005, 127,
15354.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00177.
■
(14) Rhodium catalysis in C−H activation: (a) Satoh, T.; Miura, M.
Chem. - Eur. J. 2010, 16, 11212. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Song, G.; Wang, F.; Li, X.
Chem. Soc. Rev. 2012, 41, 3651.
(15) Edward, J. T.; Sheffler, R. H. J. Org. Chem. 1985, 50, 4855.
(16) (a) Qin, C.; Feng, P.; Ou, Y.; Shen, T.; Wang, T.; Jiao, N. Angew.
Chem., Int. Ed. 2013, 52, 7850. (b) Muller, C.; Iverson, C. N.; Lachicotte,
R. J.; Jones, W. D. J. Am. Chem. Soc. 2001, 123, 9718.
S
Experimental details and spectral data for all products
(PDF)
X-ray data for 3aa (CCDC 1445045) (CIF)
X-ray data 3ga (CCDC 1445046) (CIF)
(17) For the mechanism of C−H alkynylation, see SI.
(18) CuII/O2 catalytic system examples: (a) Zhang, C.; Jiao, N. J. Am.
Chem. Soc. 2010, 132, 28. (b) Wang, Z.-Q.; Zhang, W.-W.; Gong, L.-B.;
Tang, R.-Y.; Yang, X.-H.; Liu, Y.; Li, J.-H. Angew. Chem., Int. Ed. 2011,
50, 8968. (c) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q.
Angew. Chem., Int. Ed. 2011, 50, 5678.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chemlt2015@nynu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the financial support from Nanyang
Normal University (ZX2016016).
■
REFERENCES
■
(1) (a) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
(b) Lagoja, I. M. Chem. Biodiversity 2005, 2, 1. (c) Jessen, H. J.;
Gademann, K. Nat. Prod. Rep. 2010, 27, 1168.
D
DOI: 10.1021/acs.orglett.6b00177
Org. Lett. XXXX, XXX, XXX−XXX